Mechanistic Characterization of Uterine Pain (MCUP)

STATUS

Recruiting
End date

Aug 31, 2024
participants needed

214
sponsor

NorthShore University HealthSystem

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Updated on 17 June 2022

See if I qualify

pain relief

naproxen

mediators

MRI

NSAID

MRI Scan

pelvic mri

prostaglandin

pelvic pain

endometriosis

leiomyoma

dyspareunia

primary dysmenorrhea

cramp

adenomyosis

uterine pain

prostanoids

Accepts healthy volunteers

Summary

There are limited treatment options for management of dysmenorrhea, and the physiological processes they affect are not completely understood. For example, NSAIDs are effective in reducing menstrual pain in some women by inhibition of prostaglandin synthesis, but whether those effects are mediated by affecting contractility, perfusion, or hypoxemia is unknown. Understanding how these drugs relieve menstrual pain (and why they fail) would be of substantial clinical significance. Given the foregoing, Two Specific Aims are proposed:

Aim #1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI scans of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. The investigators will include cohorts of women with imaging diagnosed leiomyoma and surgically-confirmed endometriosis to evaluate the contribution of structurally identifiable factors. Based on preliminary data, the investigators anticipate finding four phenotypes with menstrual pain related to: 1) myometrial activity, 2) inadequate perfusion and/or oxygenation, 3) a combination of phenotypes 1 & 2, and 4) a non-uterine source.

Aim #2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. In women with primary dysmenorrhea, the investigators will acquire pelvic MRI scans and evaluate self-reported menstrual cramping pain before and after administration of randomized naproxen or placebo.

Naproxen could principally affect one or more potential sources of uterine pain such as myometrial activity, perfusion, and/or oxygenation. The investigators will corroborate preliminary data findings, which suggest menstrual phenotypes with myometrial activity will be more likely to respond. Conversely, Aim 2 will also elucidate the mechanisms responsible for inadequate pain relief from naproxen.

Bioavailability of naproxen levels and other molecules associated with NSAID-resistance will be evaluated from the serum of participants after taking naproxen using HPLC-MS.

Description

Due to a lack of noninvasive tools to study uterine physiology, the root causes of menstrual cramping pain within primary dysmenorrhea and secondary dysmenorrhea (leiomyoma, endometriosis, adenomyosis) remain unknown. This pain does not respond to typical over-the-counter anti-inflammatories in 15% of women and is a leading risk factor for developing challenging chronic pelvic pain disorders. In order to guide drug discoveries and create personalized treatment approaches, it is essential to unveil the underlying mechanisms of dysmenorrhea. Our research program has focused on key gaps in our knowledge of uterine physiology, such as the contributions of uterine contractions, perfusion, and oxygenation to menstrual pain. Although these factors are strongly implicated in this debilitating pain disorder, confirmatory human data is still needed. Such research would be quite timely, as numerous drug candidates targeting these potential mechanisms already exist. Our collaborative team has developed MRI-based tools to noninvasively and dynamically measure uterine contractions, perfusion, relative tissue oxygenation, and metabolites indicative of anaerobic respiration. The investigators have also pioneered methods that link spontaneous pain report to simultaneous uterine events. Together, these methods will allow us to evaluate the contribution of contractility, perfusion, or hypoxemia to menstrual pain. Notably, our preliminary data supports our central hypothesis that menstrual pain is associated with different phenotypes involving myometrial hypercontractility, impaired uterine perfusion, uterine hypoxemia, or a non-uterine source. Since understanding how current anti-inflammatory medications relieve or prevent pain (and why they fail) is valuable for the development of improved treatment strategies, the investigators will also investigate the effects of naproxen on uterine physiology in women with menstrual pain. To test our hypothesized contributions of altered uterine muscle activity, perfusion, and oxygenation on pain, The investigators propose: Aim 1: Characterize menstrual pain phenotypes associated with impairments in myometrial activity, perfusion, and/or oxygenation. Continuous MRI sequences of the uterus will be performed with simultaneous measurement of self-reported pain in healthy women and those experiencing menstrual pain. A cohort of women with leiomyoma and endometriosis will also be analyzed to evaluate the contribution of myometrial activity, perfusion, and oxygenation in women with structurally identifiable conditions. Aim 2: Evaluate the effects of naproxen on myometrial activity, perfusion, and/or oxygenation with respect to pain relief. Preliminary data suggests unresolved myometrial activity and inadequate naproxen absorption are associated with insufficient pain relief. Evaluating the naproxen-dependent effects of uterine physiology will provide a foundation for diagnostic tests to indicate relevant personalized treatment for patients that have failed conventional treatments. Further translation of these studies could advance mechanisms for discovery in other chronic pelvic pain conditions and uterine disorders such as idiopathic preterm labor and unexplained infertility.

Details

Condition	Dysmenorrhea (Disorder), Dysmenorrhea Primary, Dysmenorrhea Secondary, Endometrial Diseases, Leiomyoma, Fibroid Uterus
Treatment	Naproxen sodium
Clinical Study Identifier	NCT04145518
Sponsor	NorthShore University HealthSystem
Last Modified on	17 June 2022

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Inclusion Criteria for Primary Dysmenorrhea Group: All cases (n=70) will have pain in the
	region between the umbilicus and the perineum, above the level of the inguinal ligament
	and rate their average pain greater than or equal to 6/10 (0 = no pain; 10 = worst
	imaginable pain) during menses when not using NSAIDs. The investigators will use strict
	inclusion criteria and verification with structural MRI to ensure patients with primary
	dysmenorrhea most likely do not have endometriosis, leiomyoma, or adenomyosis as described
	below. It is not possible to reliably evaluate superficial endometriosis with MRI
	(Nisenblat et al., 2016), but suspicious cases for deep infiltrating endometriosis will be
	confirmed by the radiologists who routinely evaluate MRIs for our gynecological surgical
	service. Although it is impossible to rule out endometriosis without surgery, in select
	cases The investigators will use clinical exams and criteria supported by decision trees
	(Eskenazi et al., 2001; Chapron et al., 2005, 2011; Vercellini et al., 2007) that suggest
	the detection of endometriosis stage 2 or higher would be unlikely (<15%) in this
	population. Participants with dysmenorrhea that rate their bowel pain, dyspareunia, or
	non-menstrual pelvic pain equal to or greater than 40 on 0-100 visual analog pain scale on
	the McGill Pain Questionnaire will be given the option to participate in an additional
	clinical exam visit. To reduce the likelihood of comorbid endometriosis, primary
	dysmenorrhea participants with symptoms of endometriosis described above, will be required
	to have a negative clinical exam and no immediate family history of endometriosis to
	qualify for final analyses
	Inclusion Criteria for Leiomyomata Group: The investigators will also study participants
	with leiomyomata (n=20) because it is a frequent cause of menstrual pain and will often be
	identified in disqualified primary dysmenorrhea participants. Leiomyomata (nondegenerated)
	will be diagnosed by foci homogeneously hypointense on T2, but isointense relative to
	myometrium on T1 according to standard definitions (Kubik-Huch et al., 2018). To reduce
	variability within this category, the investigators will restrict enrollment to small to
	medium sized intramural leiomyomata (30 to 150 cm3 combined volume). The investigators
	anticipate 10 participants with leiomyomata will be identified from incidental MRI during
	this study, while 10 more will be recruited from advertisements and our clinic. A smaller
	cohort is studied here because the main purpose of this group is to establish whether the
	physiological basis for menstrual pain in women with leiomyomata is significantly different
	than women with primary dysmenorrhea. Participants with leiomyomata, who are also
	symptomatic with surgically diagnosed endometriosis will be excluded
	Inclusion Criteria for Endometriosis Group: Participants without leiomyomata, but
	symptomatic for endometriosis (n=20) will be enrolled before planned surgical excision
	(follow-up surgery from an earlier diagnosis). The investigators will confirm a diagnosis
	of Stage 2, 3, or 4 endometriosis following surgery. For the patients without confirmed
	abnormal surgical findings for endometriosis with dysmenorrhea will be considered as
	primary dysmenorrhea cases. Dr. Tu's pelvic pain division performs over 100 laparoscopic
	pain evaluations annually (many with deep infiltrating disease) enabling us to characterize
	MRI signals in surgically confirmed endometriosis patients. A smaller cohort is studied
	here because the main purpose of this group is to establish whether the physiological basis
	for menstrual pain in women with endometriosis is significantly different than women with
	primary dysmenorrhea
	Inclusion Criteria for Healthy Controls: Healthy control cases (n=20) must rate their
	average menstrual pain < =2/10 over that past 6 months (without NSAID use) and have no
	other concurrent pain diagnoses or leiomyomata. Their lack of concurrent pain diagnoses
	will be confirmed with questionnaires (NIH PROMIS scales, Rome Foundation IBS criteria
	(Palsson et al., 2016), AUA bladder pain syndrome criteria (Hanno et. al. 2012), and the
	Complex Medical Symptom Inventory (Williams and Schilling, 2009) and a medical exam screen
	Healthy controls and participants with primary dysmenorrhea will be ratio-metrically
	age-matched with comparable pregnancy history to ensure similar demographics between
	groups
Exclusion Criteria
	Age restrictions for all study participants: Regularly menstruating women (age 18-45) will
	be identified using our well-tested community-wide recruitment strategy, including
	approaching our division's busy gynecological disorders clinic, and the departments of
	Ob/Gyn at NorthShore and the University of Chicago. Although women above the age of 45 can
	have menstrual pain, irregularities in perimenopause could cause confounding effects on
	uterine physiology and scheduling difficulty. Similarly, irregularities in menstruation
	ovulation, and pain levels in participants under age 18 could potentially detract from
	meaningful interpretation of phenotypes (Seidman et al., 2018). Additionally, before age
	the uterus is still developing and substantially increasing in size (Porcu et al
	Verguts et al., 2013). Thus, to limit potential confounding effects, participants
	under the age of 18 will be investigated in a separate study
	Menstruation-related exclusion criteria for all study participants: The investigators will
	exclude certain participants with conditions associated with the absence of regular menses
	such as polycystic ovarian syndrome, pregnancy, current use of any continuous hormonal
	medication or contraceptive, or Asherman's syndrome
	MRI-related or participation related exclusion criteria for all study participants
	The investigators will exclude participants with criteria that would affect our ability to
	obtaining meaningful MRI data such as
	presence of an intrauterine device (IUD). The use of an IUD potentially affects
	interpretability of MRI because it creates an imaging artifact in the endometrium
	extending to the myometrium
	any diagnosed condition that would preclude investigation with MRI (e.g
	claustrophobia)
	Exclusion criteria for known factors that affect the interpretability of the data for all
	study participants
	inability to read or comprehend the informed consent written in English
	history of metallic implants
	history of metallic injury
	BMI >40
	allergy or inability to tolerate naproxen
	thyroid dysfunction
	adrenal dysfunction
	Provisional exclusion for primary analyses for all study participants: Acute or chronic
	renal disorders
	conditions associated with pelvic pain with a defined anatomical cause other than
	liver disorders
	endometriosis or leiomyoma (e.g., pathological ovarian cysts, significant persistent
	coagulopathy
	hydro/hematosalpinx, untreated pelvic inflammatory disease, active pelvic or abdominal
	prolactinoma
	malignancies, Mullerian anomalies, or stage 3 uterine prolapse), and comorbid diagnosis of
	von Willebrand disease
	significant leiomyoma and endometriosis
	platelet disorders
	Note: these exclusion criteria may be incidentally discovered after the MRI scan and
	diabetic neuropathy
	confirmed with a radiologist's or Dr. Tu's diagnosis
	gastrointestinal conditions or surgeries that would affect naproxen absorption
	Provisional exclusion for adenomyosis group: Because the frequency of adenomyosis is low or
	active genitourinary or sexually transmitted infection
	unknown, and may consist of multiple subtypes resulting in heterogeneity and inadequate
	statistical power, adenomyosis patients are not a planned study group and diagnosed cases
	will be initially excluded from recruitment. Focal and diffuse adenomyosis will be excluded
	by guidelines (Chapron et al., 2017) adapted from the Kishi criteria (Kishi et al., 2012)
	maximal junctional zone thickness exceeding 12 mm, a ratio of junctional zone thickness to
	myometrium exceeding 40%, or high-intensity foci within the myometrium. If a substantial
	number of adenomyosis participants participate, as discovered after-the-fact with MRI
	results will be analyzed
	Intermediate levels of dysmenorrhea pain exclusion: Participants with mild menstrual pain
	(between 3 and 5 on a 0-10 scale) will be excluded. Our prior experience with this cohort
	(Westling et al., 2013) suggests that The investigators may encounter a floor effect when
	studying the effectiveness of NSAIDs. Also, since this cohort is most likely to respond to
	NSAIDs, it is imperative The investigators study the mechanisms of the most severe
	sufferers of refractory menstrual pain

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Mechanistic Characterization of Uterine Pain (MCUP)